Rapid antidepressant-like effect of non-hallucinogenic psychedelic analog lisuride, but not hallucinogenic psychedelic DOI, in lipopolysaccharide-treated mice

Classical psychedelics with 5-hydroxytryptamine-2A receptor (5-HT_2AR) agonism have rapid antidepressant actions in patients with depression. However, there is an ongoing debate over the role of 5-HT_2AR in the antidepressant-like actions of psychedelics. In this study, we compared the effects of DOI (2,5-dimethoxy-4-iodoamphetamine: a hallucinogenic psychedelic drug with potent 5-HT_2AR agonism), lisuride (non-hallucinogenic psychedelic analog with 5-HT_2AR and 5-HT_1AR agonisms), and the novel antidepressant (R)-ketamine on depression-like behavior and the decreased dendritic spine density in the brain of lipopolysaccharide (LPS)-treated mice. Saline (10 ml/kg), DOI (2.0 mg/kg), lisuride (1.0 mg/kg), or (R)-ketamine (10 mg/kg) was administered intraperitoneally to LPS (0.5 mg/kg, 23 h before)-treated mice. Both lisuride and (R)-ketamine significantly ameliorated the increased immobility time of forced swimming test, and the decreased dendritic spine density in the prelimbic region of medial prefrontal cortex, CA3 and dentate gyrus of hippocampus of LPS-treated mice. In contrast, DOI did not improve these changes produced after LPS administration. This study suggests that antidepressant-like effect of lisuride in LPS-treated mice is not associated with 5-HT_2AR-related psychedelic effects. It is, therefore, unlikely that 5-HT_2AR may play a major role in rapid-acting antidepressant actions of psychedelics although further detailed study is needed.